Sustained delivery of an active agent using an implantable system

ABSTRACT

The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of a provisionalapplication (serial number as yet unknown) which was filed on Feb. 2,1996 as regular U.S. application Ser. No. 08/595,761 and converted to aprovisional application via a petition filed on Jan. 21, 1997.

TECHNICAL FIELD

This invention is related to the sustained delivery of a biologicallyactive agent. More particularly, the invention is directed to animplantable delivery system for the prolonged delivery of an activeagent to a fluid environment in a natural or artificial body cavity.

BACKGROUND OF THE INVENTION

Treatment of disease by prolonged delivery of an active agent at acontrolled rate has been a goal in the drug delivery field. Variousapproaches have been taken toward delivering the active agents.

One approach involves the use of implantable diffusional systems. Forexample, subdermal implants for contraception are described by Philip D.Darney in Current Opinion in Obstetrics and Gynecology 1991, 3:470-476.Norplant® requires the placement of 6 levonorgestrel-filled silasticcapsules under the skin. Protection from conception for up to 5 years isachieved. The implants operate by simple diffusion, that is, the activeagent diffuses through the polymeric material at a rate that iscontrolled by the characteristics of the active agent formulation andthe polymeric material. Darney further describes biodegradable implants,namely Capranor™ and norethindrone pellets. These systems are designedto deliver contraceptives for about one year and then dissolve. TheCapranor™ systems consist of poly(ε-caprolactone) capsules that arefilled with levonorgestrel and the pellets are 10% pure cholesterol with90% norethindrone.

Implantable infusion pumps have also been described for delivering drugsby intravenous, intra-arterial, intrathecal, intraperitoneal,intraspinal and epidural pathways. The pumps are usually surgicallyinserted into a subcutaneous pocket of tissue in the lower abdomen.Systems for pain management, chemotherapy and insulin delivery aredescribed in the BBI Newsletter, Vol. 17, No. 12, pages 209-211,December 1994. These systems provide for more accurately controlleddelivery than simple diffusional systems.

One particularly promising approach involves osmotically driven devicessuch as those described in U.S. Pat. Nos. 3,987,790, 4,865,845,5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,234,692 and 5,234,693which are incorporated by reference herein. These devices can beimplanted into an animal to release the active agent in a controlledmanner for a predetermined administration period. In general, thesedevices operate by imbibing fluid from the outside environment andreleasing corresponding amounts of the active agent.

The above-described devices have been useful for delivering activeagents to a fluid environment of use. Although these devices have foundapplication for human and veterinary purposes, there remains a need fordevices that are capable of delivering active agents, particularlypotent unstable agents, reliably to a human being at a controlled rateover a prolonged period of time.

SUMMARY OF THE INVENTION

Implantable osmotic systems for delivery of an active agent to an animalare well known. Adaptation of these systems for human use raises anumber of difficult issues. The size of the device may need to bedecreased for human implantation. The strength of the device must besufficient to ensure a robust system. Accurate and reproducible deliveryrates and durations must be ensured and the period from implantation tostart-up of delivery must be minimized. The active agent must return itspurity and activity for extended periods of time at the elevatedtemperatures encountered in the body cavity.

Accordingly, in one aspect, the invention is a fluid-imbibing device fordelivering an active agent formulation to a fluid environment of use.The device comprises a water-swellable, semipermeable material that isreceived in sealing relationship with the interior surface at one end ofan impermeable reservoir. The device further contains an active agent tobe displaced from the device when the water-swellable material swells.

In another aspect, the invention is directed to an implantable devicefor delivering an active agent to a fluid environment of use. The devicecomprises a reservoir and a back diffusion regulating outlet in a matingrelationship. The flow path of the active agent comprises a pathwayformed between the mating surfaces of the back diffusion regulatingoutlet and the reservoir.

In yet another aspect, the present invention is directed to a device forstoring an active agent in a fluid environment of use during apredetermined administration period, the device comprising a reservoircontaining an active agent. The reservoir is impermeable and formed atleast in part from a metallic material. The portion of the reservoircontacting the active agent is non-reactive with the active agent, andis formed of a material selected from the group consisting of titaniumand its alloys.

In a further aspect, the invention is an implantable fluid-imbibingactive agent delivery system that comprises an impermeable reservoir.The reservoir contains a piston that divides the reservoir into anactive agent containing chamber and a water-swellable agent containingchamber. The active agent containing chamber is provided with aback-diffusion regulating outlet. The water-swellable agent containingchamber is provided with a semipermeable plug. Either the plug or theoutlet is releasable from the reservoir at an internal pressure that islower than the maximum osmotic pressure generated by the water-swellableagent.

The invention is further directed to a fluid-imbibing implantable activeagent delivery system where the time to start-up of delivery is lessthan 10% of the predetermined administration period.

In another aspect, the invention is directed to a method for preparing afluid-imbibing implantable active agent delivery system. The methodcomprises injection molding a semipermeable plug into the end of animpermeable reservoir such that the plug is protected by the reservoir.

In still another aspect, the invention is directed to an impermeableactive agent delivery system for delivering an active agent that issusceptible to degradation. The reservoir contains a piston that dividesthe reservoir into a water-swellable agent chamber and an active agentchamber. The open end of the water-swellable agent chamber contains asemipermeable membrane and the open end of the active agent chambercontains a back-diffusion regulating outlet. The system effectivelyseals the active agent chamber and isolates it from the environment ofuse.

In a further aspect, the invention is directed to a back-diffusionregulating outlet useful in an active agent delivery system. The outletdefines a flow path wherein the length, interior cross-sectional shapeand area provide for an average linear velocity of active agent that ishigher than the linear inward flow of fluid in the environment of use.

The invention is also directed to a semipermeable plug useful in anactive agent delivery system. The plug is water-swellable and mustexpand linearly in the delivery system to commence pumping uponinsertion of the system into the fluid environment of use.

The invention is further directed to implantable delivery systems usefulfor delivering leuprolide.

DESCRIPTION OF THE DRAWINGS

The figures are not drawn to scale, but are set forth to illustratevarious embodiments of the invention. Like numbers refer to likestructures.

FIGS. 1 and 2 are partial cross-sectional views of two embodiments ofthe delivery device of the invention.

FIG. 3 is an enlarged cross-sectional view of the back-diffusionregulating outlet of FIG. 1.

FIG. 4 is a graph that shows the effect of orifice diameter and lengthon drug diffusion.

FIGS. 5, 6, 7 and 8 are enlarged cross-sectional views of furtherembodiments of the semipermeable plug end of the reservoir according tothe invention.

FIGS. 9, 10 and 11 are graphs of release rates for systems withleuprolide (FIG. 9) and with blue dye and with different membranes(FIGS. 10 and 11).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a device for the delivery of an activeagent to a fluid environment of use in which the active agent must beprotected from the fluid environment until it is delivered. Prolongedand controlled delivery is achieved.

Definitions

The term “active agent” intends the active agent(s) optionally incombination with pharmaceutically acceptable carriers and, optionallyadditional ingredients such as antioxidants, stabilizing agents,permeation enhancers, etc.

By a “predetermined administration period” is intended a period ofgreater than 7 days, often between about 30 days and 2 years, preferablygreater than about 1 month and usually between about 1 month and 12months.

By the time to “start-up” of delivery is intended the time frominsertion into the fluid environment of use until the active agent isactually delivered at a rate not less than approximately 70% of theintended steady-state rate.

The term “impermeable” intends that the material is sufficientlyimpermeable to environmental fluids as well as ingredients containedwithin the dispensing device such that the migration of such materialsinto or out of the device through the impermeable device is so low as tohave substantially no adverse impact on the function of the deviceduring the delivery period.

The term “semipermeable” intends that the material is permeable toexternal fluids but substantially impermeable to other ingredientscontained within the dispensing device and the environment of use.

As used herein, the terms “therapeutically effective amount” or“therapeutically effective rate” refer to the amount or rate of theactive agent needed to effect the desired biologic or pharmacologiceffect.

The active agent delivery devices of the invention find use where theprolonged and controlled delivery of an active agent is desired. In manycases the active agent is susceptible to degradation if exposed to theenvironment of use prior to delivery and the delivery devices protectthe agent from such exposure.

FIG. 1 shows one embodiment of the device according to the invention. InFIG. 1 a fluid-imbibing system 10 is shown that comprises an impermeablereservoir 12. The reservoir 12 is divided into two chambers by a piston16. The first chamber 18 is adapted to contain an active agent and thesecond chamber 20 is adapted to contain a fluid-imbibing agent. Aback-diffusion regulating outlet 22 is inserted into the open end of thefirst compartment 18 and a water-swellable semipermeable plug 24 isinserted into the open end of the second chamber 20. In FIG. 1, theback-diffusion regulating outlet 22 is shown as a male threaded memberin a mating relationship with the smooth interior surface of thereservoir 12 thereby forming therebetween helical flow path 34. Thepitch (x), the amplitude (y), and the cross-sectional area and shape ofthe helical path 34 formed between the mating surfaces of theback-diffusion regulating outlet 22 and the reservoir 12 as shown inFIG. 3 are factors that affect both the efficiency of path 34 preventingback-diffusion of external fluid into the formulation in chamber 18 andthe back pressure in the device. The geometry of outlet 22 preventswater diffusion into the reservoir. In general, it is desired that thesecharacteristics be selected so that the length of the helical flow path34 and the velocity of flow of active agent therethrough is sufficientto prevent back-diffusion of external fluid through the flow path 34without significantly increasing the back pressure, so that, followingstart-up, the release rate of the active agent is governed by theosmotic pumping rate.

FIG. 2 is a second embodiment of the device of the invention with areservoir 12, piston 16 and plug 26. In this embodiment, the flow path36 is formed between a threaded back-diffusion regulating outlet 40 andthreads 38 formed on the interior surface of the reservoir 12. Theamplitudes of the threaded portions of the back-diffusion regulatingoutlet 40 and reservoir 12 are different so that a flow path 36 isformed between the reservoir 12 and the back-diffusion regulating outlet40.

The water-swellable semipermeable plugs 24 and 26 shown in FIGS. 1 and 2respectively are inserted into the reservoir such that the reservoirwall concentrically surrounds and protects the plug. In FIG. 1, the topportion 50 of the plug 24 is exposed to the environment of use and mayform a flanged end cap portion 56 overlaying the end of reservoir 12.The semipermeable plug 24 is resiliently engaged with the interiorsurface of the reservoir 12 and in FIG. 1 is shown to have ridges 60that serve to frictionally engage the semipermeable plug 24 with theinterior of reservoir 12. In addition, the ridges 60 serve to produceredundant circumferential seals that function before the semipermeableplug 24 expands due to hydration. The clearance between ridges 60 andthe interior surface of the reservoir 12 prevents hydration swellingfrom exerting stresses on the reservoir 12 that can result in tensilefailure of the reservoir 12 or compression or shear failure of the plug24. FIG. 2 shows a second embodiment of the semipermeable plug 26 wherethe plug is injection molded into the top portion of the reservoir andwhere the top of the semipermeable plug 26 is flush with the top 62 ofthe reservoir 12. In this embodiment, the diameter of the plug issubstantially less than the diameter of the reservoir 12. In bothembodiments the plugs 24 and 26 will swell upon exposure to the fluid inbody cavity forming an even tighter seal with the reservoir 12.

The novel configurations of the components of the above-describedembodiments provide for implantable devices that are uniquely suited forimplantation into humans and can provide delivery devices which arecapable of storing unstable formulations at body temperatures forextended periods of time, which devices have start-up times of less than10% of the administration period and can be designed to be highlyreliable and with predictable fail safe modes.

Reservoir 12 must be sufficiently strong to ensure that it will notleak, crack, break or distort so as to expel its active agent contentsunder stresses it would be subjected to during use while beingimpermeable. In particular, it should be designed to withstand themaximum osmotic pressure that could be generated by the water-swellablematerial in chamber 20. Reservoir 12 must also be chemically inert andbiocompatible, that is, it must be non-reactive with the active agentformulation as well as the body. Suitable materials generally comprise anon-reactive polymer or a biocompatible metal or alloy. The polymersinclude acrylonitrile polymers such as acrylonitrile-butadiene-styreneterpolymer, and the like; halogenated polymers such aspolytetrafluoroethylene, polychlorotrifluoroethylene, copolymertetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone;polycarbonate; polyethylene; polypropylene; polyvinylchloride-acryliccopolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene;and the like. The water vapor transmission rate through compositionsuseful for forming the reservoir are reported in J. Pharm. Sci., Vol.29, pp. 1634-37 (1970), Ind. Eng. Chem., Vol. 45, pp. 2296-2306 (1953);Materials Engineering, Vol. 5, pp. 38-45 (1972); Ann. Book of ASTMStds., Vol. 8.02, pp. 208-211 and pp. 584-587 (1984); and Ind. and Eng.Chem., Vol. 49, pp. 1933-1936 (1957). The polymers are known in theHandbook of Common Polymers by Scott and Roff, CRC Press, ClevelandRubber Co., Cleveland, Ohio. Metallic materials useful in the inventioninclude stainless steel, titanium, platinum, tantalum, gold and theiralloys as well as gold-plated ferrous alloys, platinum-plated ferrousalloys, cobalt-chromium alloys and titanium nitride coated stainlesssteel. A reservoir made from titanium or a titanium alloy having greaterthan 60%, often greater than 85% titanium is particularly preferred forthe most size-critical applications, for high payload capability and forlong duration applications and for those applications where theformulation is sensitive to body chemistry at the implantation site orwhere the body is sensitive to the formulation. Preferred systemsmaintain at least 70% active agent after 14 months at 37° C. and have ashelf stability of at least about 9 months, or more preferably at leastabout two years, at 2-8° C. Most preferably, systems may be stored atroom temperature. In certain embodiments, and for applications otherthan the fluid-imbibing devices specifically described, where unstableformulations are in chamber 18, particularly protein and/or peptideformulations, the metallic components to which the formulation isexposed must be formed of titanium or its alloys as described above.

The devices of this invention provide a sealed chamber 18 whicheffectively isolates the formulation from the fluid environment. Thereservoir 12 is made of a rigid, impermeable and strong material. Thewater-swellable semipermeable plug 24 is of a lower durometer materialand will conform to the shape of the reservoir to produce a liquid-tightseal with the interior of reservoir 12 upon wetting. The flow path 34isolates chamber 18 from back-diffusion of environmental fluid. Piston16 isolates chamber 18 from the environmental fluids that are permittedto enter chamber 20 through semipermeable plugs 24 and 26 such that, inuse at steady-state flow, active agent is expelled through outlet 22 ata rate corresponding to the rate at which water from the environmentflows into the water-swellable material in chamber 20 throughsemipermeable plugs 24 and 26. As a result, the plug and the activeagent formulation will be protected from damage and their functionalitywill not be compromised even if the reservoir is deformed. In addition,the use of sealants and adhesives will be avoided and the attendantissues of biocompatibility and ease of manufacture resolved.

Materials from which the semipermeable plug are made are those that aresemipermeable and that can conform to the shape of the reservoir uponwetting and adhere to the rigid surface of the reservoir. Thesemipermeable plug expands as it hydrates when placed in a fluidenvironment so that a seal is generated between the mating surfaces ofthe plug and the reservoir. The strength of the seals between thereservoir 12 and the outlet 22 and the reservoir 12 and the plugs 24 and26 can be designed to withstand the maximum osmotic pressure generatedby the device. In a preferred alternative, the plugs 24 and 26 may bedesigned to withstand at least 10× the osmotic agent compartment 20operating pressure. In a further alternative the plugs 24 and 26 may bereleasable from the reservoir at an internal pressure that is lower thanthe pressure needed to release the back diffusion regulating outlet. Inthis fail safe embodiment, the water-swellable agent chamber will beopened and depressurized, thus avoiding dispelling the diffusionregulating outlet and attendant release of a large quantity of theactive agent. In other cases, where a fail-safe system requires therelease of the active agent formulation rather than the water-swellableagent formulation, the semipermeable plug must be releasable at apressure that is higher than the outlet.

In either case, the semipermeable plug must be long enough to sealablyengage the reservoir wall under the operating conditions, that is, itshould have an aspect ratio of between 1:10 and 10:1 length to diameter,preferably at least about 1:2 length to diameter, and often between 7:10and 2:1. The plug must be able to imbibe between about 0.1% and 200% byweight of water. The diameter of the plug is such that it will sealinglyfit inside the reservoir prior to hydration as a result of sealingcontact at one or more circumferential zones and will expand in placeupon wetting to form an even tighter seal with the reservoir. Thepolymeric materials from which the semipermeable plug may be made varybased on the pumping rates and device configuration requirements andinclude but are not limited to plasticized cellulosic materials,enhanced polymethylmethacrylate such as hydroxyethylmethacrylate (HEMA)and elastomeric materials such as polyurethanes and polyamides,polyether-polyamide copolymers, thermoplastic copolyesters and the like.

The piston 16 isolates the water-swellable agent in chamber 20 from theactive agent in chamber 18 and must be capable of sealably moving underpressure within reservoir 12. The piston 16 is preferably made of amaterial that is of lower durometer than the reservoir 12 and that willdeform to fit the lumen of the reservoir to provide a fluid-tightcompression seal with the reservoir 12. The materials from which thepiston are made are preferably elastomeric materials that areimpermeable and include but are not limited to polypropylene, rubberssuch as EPDM, silicone rubber, butyl rubber, and the like, andthermoplastic elastomers such as plasticized polyvinylchloride,polyurethanes, Santoprene®, C-Flex® TPE (Consolidated PolymerTechnologies Inc.), and the like. The piston may be of a self-loading orcompression-loaded design.

The back-diffusion regulating outlet 22 forms the delivery pathwaythrough which the active agent flows from the chamber 18 to theimplantation site where absorption of the active agent takes place. Theseal between the outlet 22 and the reservoir 12 can be designed towithstand the maximum osmotic pressure generated within the device or tofail-safe in the modes described above. In a preferred embodiment, thepressure required to release back-diffusion regulating outlet 22 is atleast 10× the pressure required to move piston 16 and/or at least 10×the pressure in chamber 18.

The exit flow path of the active agent is the pathway 34 formed betweenthe mating surfaces of the back-diffusion regulating outlet 22 and thereservoir 12. The pathway length, interior cross-sectional shape andarea of the outlet path 34 or 36 are chosen such that the average linearvelocity of the exiting active agent is higher than that of the linearinward flux of materials in the environment of use due to diffusion orosmosis, thereby attenuating or moderating back-diffusion and itsdeleterious effects of contaminating the interior of the pump,destabilizing, diluting, or otherwise altering the formulation. Therelease rate of active agent can be modified by modifying the outletpathway geometry, which relationship is shown below.

The convective flow of active agent out of outlet 22 is set by thepumping rate of the system and the concentration of active agent inchamber 20 and can be represented as follows:

Q _(ca)=(Q)(C _(a))   (1)

where

-   -   Q_(ca) is the convective transport of agent A in mg/day    -   Q is the overall convective transport of the agent and its        diluents in cm³/day    -   C_(a) is the concentration of agent A in the formulation within        chamber 20 in mg/cm³

The diffusive flow of agent A through the material in the outlet 22 is afunction of agent concentration, cross-sectional configuration of flowpath 34 or 36, agent diffusivity and length of flow path 34 or 36, andcan be represented as follows:

Q _(da) =Dπr ² ΔC _(a) /L   (2)

where

-   -   Q_(da) is the diffusive transport of agent A in mg/day    -   D is the diffusivity through the material in path 34 or 36 in        cm²day    -   r is the effective inner radius of the flow path in cm    -   ΔC_(a) is the difference between the concentration of agent A in        the reservoir and in the body outside of the outlet 22 in mg/cm³    -   L is the length of the flow path in cm

In general, the concentration of agent in the reservoir is much greaterthan the concentration of agent in the body outside of the orifice suchthat the difference, ΔC_(a) can be approximated by the concentration ofagent within the reservoir, C_(a).

Q _(da) =Dπr ² C _(a) /L   (3)

It is generally desirable to keep the diffusive flux of agent at lessthan 10% of the convective flow. This is represented as follows:

Q _(da) /Q _(ca) =Dπr ² C _(a) /QC _(a) L=Dπr ² /QL≦0.1   (4)

Equation 4 indicates that the relative diffusive flux decreases withincreasing volumetric flow rate and path length and increases withincreasing diffusivity and channel radius and is independent of drugconcentration. Equation 4 is plotted in FIG. 4 as a function of length(L) and diameter (d) for D=2×10⁻⁶ cm²/sec and Q=0.36 μl/day.

The diffusive flux of water where the orifice opens into chamber 18 canbe approximated as:

Q _(wd)(res)=C _(o) Qe ^((−QL/DwA ))   (5)

where

C_(o) is the concentration profile of water in mg/cm³

Q is the mass flow rate in mg/day

L is the length of the flow path in cm

D_(w) is the diffusivity of water through the material in the flow pathin cm²/day

A is the cross-sectional area of the flow path in cm²

The hydrodynamic pressure drop across the orifice can be calculated asfollows:

$\begin{matrix}{{\Delta \; P} = \frac{8\mspace{11mu} {QL}\; \mu}{\pi \; r^{4}}} & (6)\end{matrix}$

Simultaneously solving equations (4), (5) and (6) gives the values shownin Table 1 where:

-   -   Q=0.38 μl/day    -   C_(a)=0.4 mg/μl    -   L=5 cm    -   D_(a)=2.00 E-06 cm²/sec    -   μ=5.00 E+02 cp    -   C_(w0)=0 mg/μl    -   D_(w)=6.00 E+06 cm²/sec

TABLE 1 Drug Diffusion & Pumping Effective Pump rate Diffusion WaterIntrusion Pressure Drop Orifice dia Cross Sec QC_(a) QD_(a) Diff/ConvQD_(w) Qdw delta P (mil) area (mm2) mg/day mg/day QD_(a)/QC_(a) mg/daymg/year psi 1 0.00051 0.152 0.0001 0.0005 0 0 1.55800 2 0.00203 0.1520.0003 0.0018 1.14E−79 4.16E−77 0.09738 3 0.00456 0.152 0.0006 0.00414.79E−36 1.75E−33 0.01923 4 0.00811 0.152 0.0011 0.0074 8.89E−213.25E−18 0.00609 5 0.01267 0.152 0.0018 0.0115 1.04E−13 3.79E−11 0.002496 0.01824 0.152 0.0025 0.0166 7.16E−10 2.61E−07 0.00120 7 0.02483 0.1520.0034 0.0226 1.48E−07  5.4E−05 0.00065 8 0.03243 0.152 0.0045 0.0295 4.7E−06 0.001715 0.00038 9 0.04105 0.152 0.0057 0.0373 5.04E−050.018381 0.00024 10 0.05068 0.152 0.0070 0.0461 0.000275 0.1002630.00016 11 0.06132 0.152 0.0085 0.0558 0.000964 0.351771 0.00011 120.07298 0.152 0.0101 0.0664 0.002504 0.913839 0.00008 13 0.08564 0.1520.0118 0.0779 0.005263 1.921027 0.00005 14 0.09933 0.152 0.0137 0.09030.00949 3.463836 0.00004 15 0.11402 0.152 0.0158 0.1037 0.0152695.573195 0.00003 16 0.12973 0.152 0.0179 0.1180 0.022535 8.2252240.00002 17 0.14646 0.152 0.0202 0.1332 0.031114 11.35656 0.00002 180.16419 0.152 0.0227 0.1493 0.040772 14.88166 0.00001 19 0.18295 0.1520.0253 0.1664 0.051253 18.70728 0.00001 20 0.20271 0.152 0.0280 0.18440.062309 22.7427 0.00001

The calculations indicate that an orifice diameter of between about 3and 10 mil and a length of 2 to 7 cm is optimal for a device with theoperating conditions described. In a preferred embodiment, the pressuredrop across the orifice is less than 10% of the pressure required torelease the back-diffusion regulating outlet 22.

The back-diffusion regulating outlet 22 preferably forms a helicalpathway 34 or 36 incorporating a long flow path with a means ofmechanically attaching the outlet into the reservoir without usingadhesives or other sealants. The back-diffusion regulating outlet ismade of an inert and biocompatible material selected from but notlimited to metals including but not limited to titanium, stainlesssteel, platinum and their alloys and cobalt-chromium alloys and thelike, and polymers including but not limited to polyethylene,polypropylene, polycarbonate and polymethylmethacrylate and the like.The flow path is usually between about 0.5 and 20 cm long, preferablybetween about 1 and 10 cm long and between about 0.001 and 0.020 inchesin diameter, preferably between about 0.003 and 0.015 inches to allowfor a flow of between about 0.02 and 50 μl/day, usually 0.2 to 10 μl/dayand often 0.2 to 2.0 μl/day. Additionally, a catheter or other systemmay be attached to the end of the back-diffusion regulating outlet toprovide for delivery of the active agent formulation at a site removedfrom the implant. Such systems are known in the art and are described,for example, in U.S. Pat. Nos. 3,732,865 and 4,340,054 which areincorporated herein by reference. Further, the flow path design may beuseful in systems other than the fluid-imbibing devices specificallydescribed herein.

The inventive device configurations described above also allow for aminimal period of delay from start-up to steady-state flow rate. This isaccomplished in part as a result of the configuration of thesemipermeable plug 24 or 26. As water is imbibed by the semipermeableplug, it swells. Radial expansion is limited by the rigid reservoir 12,thus the expansion must occur linearly, thereby pushing against thewater-swellable agent in chamber 18, which in turn pushes against thepiston 16. This allows pumping to commence prior to the time that waterreaches the water-swellable agent which otherwise would be requiredbefore pumping could commence. To facilitate reliable start-up, the flowpath 34 can be precharged with the active agent in chamber 18. Further,the geometry of the outlet 22 allows for initial delivery that isinfluenced by the concentration gradient of drug along the length of theoutlet. The start-up period is less than about 25% of the predetermineddelivery period and is often less than about 10% and usually less thanabout 5% of the predetermined delivery period. In a preferred embodimentfor a one year system, at least 70% of the steady-state flow rate isachieved by day 14.

The water-swellable agent formulation in chamber 20 is preferably atissue tolerable formulation whose high osmotic pressure and highsolubility propels the active agent over a long period of time whileremaining in saturated solution in the water admitted by thesemipermeable membrane. The water-swellable agent is preferably selectedfor tolerability by subcutaneous tissue, at least at pumping rates andhypothetically resulting concentrations to allow inadvertent dispensingfrom implanted devices left in the patient for a longer than labeledperiod. In preferred embodiments, the water-swellable agent should notdiffuse or permeate through the semipermeable plug 24 or 26 to anyappreciable amount (e.g., less than 8%) under normal operatingconditions. Osmotic agents, such as NaCl with appropriate tablettingagents (lubricants and binders) and viscosity modifying agents, such assodium carboxymethylcellulose or sodium polyacrylate are preferredwater-swellable agents. Other osmotic agents useful as thewater-swellable agent include osmopolymers and osmagents and aredescribed, for example, in U.S. Pat. No. 5,413,572 which is incorporatedby reference herein. The water-swellable agent formulation can be aslurry, a tablet, a molded or extruded material or other form known inthe art. A liquid or gel additive or filler may be added to chamber 20to exclude air from spaces around the osmotic engine. Exclusion of airfrom the devices should mean that delivery rates will be less affectedby nominal external pressure changes (e.g., ±7 p.s.i. (±5 a.t.m.)).

The devices of the invention are useful to deliver a wide variety ofactive agents. These agents include but are not limited topharmacologically active peptides and proteins, genes and gene products,other gene therapy agents, and other small molecules. The polypeptidesmay include but are not limited to growth hormone, somatotropinanalogues, somatomedin-C, Gonadotropic releasing hormone, folliclestimulating hormone, luteinizing hormone, LHRH, LHRH analogues such asleuprolide, nafarelin and goserelin, LHRH agonists and antagonists,growth hormone releasing factor, calcitonin, colchicine, gonadotropinssuch as chorionic gonadotropin, oxytocin, octreotide, somatotropin plusan amino acid, vasopressin, adrenocorticotrophic hormone, epidermalgrowth factor, prolactin, somatostatin, somatotropin plus a protein,cosyntropin, lypressin, polypeptides such as thyrotropin releasinghormone, thyroid stimulation hormone, secretin, pancreozymin,enkephalin, glucagon, endocrine agents secreted internally anddistributed by way of the bloodstream, and the like. Further agents thatmay be delivered include α₁antitrypsin, factor VIII, factor IX and othercoagulation factors, insulin and other peptide hormones, adrenalcortical stimulating hormone, thyroid stimulating hormone and otherpituitary hormones, interferon α, β, and δ, erythropoietin, growthfactors such as GCSF, GMCSF, insulin-like growth factor 1, tissueplasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist,tumor necrosis factor, pancreatic enzymes, lactase, cytokines,interleukin-1 receptor antagonist, interleukin-2, tumor necrosis factorreceptor, tumor suppresser proteins, cytotoxic proteins, and recombinantantibodies and antibody fragments, and the like.

The above agents are useful for the treatment of a variety of conditionsincluding but not limited to hemophilia and other blood disorders,growth disorders, diabetes, leukemia, hepatitis, renal failure, HIVinfection, hereditary diseases such as cerbrosidase deficiency andadenosine deaminase deficiency, hypertension, septic shock, autoimmunediseases such as multiple sclerosis, Graves disease, systemic lupuserythematosus and rheumatoid arthritis, shock and wasting disorders,cystic fibrosis, lactose intolerance, Crohn's diseases, inflammatorybowel disease, gastrointestinal and other cancers.

The active agents may be anhydrous or aqueous solutions, suspensions orcomplexes with pharmaceutically acceptable vehicles or carriers suchthat a flowable formulation is produced that may be stored for longperiods on the shelf or under refrigeration, as well as stored in animplanted delivery system. The formulations may include pharmaceuticacceptable carriers and additional inert ingredients. The active agentsmay be in various forms, such as uncharged molecules, components ofmolecular complexes or pharmacologically acceptable salts. Also, simplederivatives of the agents (such as prodrugs, ethers, esters, amides,etc.) which are easily hydrolyzed by body pH, enzymes, etc., can beemployed.

It is to be understood that more than one active agent may beincorporated into the active agent formulation in a device of thisinvention and that the use of the term “agent” in no way excludes theuse of two or more such agents. The dispensing devices of the inventionfind use, for example, in humans or other animals. The environment ofuse is a fluid environment and can comprise any subcutaneous position orbody cavity, such as the peritoneum or uterus, and may or may not beequivalent to the point of ultimate delivery of the active agentformulation. A single dispensing device or several dispensing devicescan be administered to a subject during a therapeutic program. Thedevices are designed to remain implanted during a predeterminedadministration period. If the devices are not removed following theadministration, they may be designed to withstand the maximum osmoticpressure of the water-swellable agent or they may be designed with abypass to release the pressure generated within the device.

The devices of the present invention are preferably rendered sterileprior to use, especially when such use is implantation. This may beaccomplished by separately sterilizing each component, e.g., by gammaradiation, steam sterilization or.sterile filtration, then asepticallyassembling the final system. Alternatively, the devices may beassembled, then terminally sterilized using any appropriate method.

Preparation of the Devices of the Invention

Reservoir 12 is prepared preferably by machining a metal rod or byextrusion or injection molding a polymer. The top portion of thereservoir may be open as shown in FIG. 1 or may contain a cavity asshown in FIG. 2.

Where the reservoir 12 is open as shown in FIG. 1, a water-swellablesemipermeable plug 24 is inserted mechanically from the outside of thereservoir without using an adhesive before or after insertion of thepiston and water-swellable agent formulation. Reservoir 12 may beprovided with grooves or threads which engage ribs or threads on plug24.

Where the reservoir 12 contains a cavity as shown in FIG. 2, the cavitymay be cylindrical in shape, as shown in FIG. 5, it may be stepped, asshown in FIG. 6, it may be helical, as shown in FIG. 7 or it may be in aspaced configuration, as shown in FIG. 8. The semipermeable plug 26 isthen injected, inserted, or otherwise assembled into the cavity so thatit forms a seal with the reservoir wall.

Following insertion of the plug 26 either mechanically, by welding or byinjection, the water-swellable agent is assembled into the reservoirfollowed by insertion of the piston, with appropriate steps taken tovent entrapped air. The active agent is filled into the device using asyringe or a precision dispensing pump. The diffusion moderator isinserted into the device, usually by a rotating or helical action, or byaxial pressing.

The following examples are illustrative of the present invention. Theyare not to be construed as limiting the scope of the invention.Variations and equivalents of these examples will be apparent to thoseof skill in the art in light of the present disclosure, the drawings andclaims herein.

EXAMPLES Example 1 Preparation of a Device with an HDPE Reservoir

A system containing leuprolide acetate for the treatment of prostatecancer was assembled from the following components:

Reservoir (HDPE) (5 mm outside diameter, 3 mm inside diameter)

Piston (Santoprene®)

Lubricant (silicone medical fluid)

Compressed osmotic engine (60% NaCl, 40% sodium carboxymethyl cellulose)

Membrane plug (Hytrel polyether-ester block copolymer, injection moldedto desired shape)

Back diffusion Regulating Outlet (polycarbonate)

Active agent (0.78 g of 60% propylene glycol and 40% leuprolide acetate)

Assembly

The piston and inner diameter of the reservoir were lightly lubricatedwith silicon medical fluid. The piston 16 was inserted into the open endof chamber 20. Two osmotic engine tablets (40 mg each) were theninserted on top of piston 16. After insertion, the osmotic engine wasflush with the end of the reservoir. The membrane plug 24 was insertedby lining up the plug with the reservoir and pushing gently until theplug was fully engaged in the reservoir. Active agent was loaded into asyringe which was then used to fill chamber 18 from its open end byinjecting the material into the open tube until the formulation was ˜3mm from the end. The filled reservoir was centrifuged (outlet end “up”)to remove any air bubbles that have been trapped in the formulationduring filling. The outlet 22 was screwed into the open end of thereservoir until completely engaged. As the outlet was screwed in, excessformulation exited out of the orifice ensuring a uniform fill.

Example 2 Insertion of the Device of Example 1

Insertion of the device of Example 1 is done under aseptic conditionsusing a trocar similar to that used in the implantation of Norplant®contraceptive implants to position the device under the skin. Theinsertion area is typically in the inside of the upper arm, 8 to 10 cmabove the elbow.

The area is anesthetized and an incision is made through the skin. Theincision is approximately 4 mm long. The trocar is inserted into theincision until the tip of the trocar is at a distance of 4 to 6 cm fromthe incision. The obturator is then removed from the trocar and thedevice of Example 1 inserted into the trocar. The device is thenadvanced to the open end of the trocar using the obturator. Theobturator is then held in position, thus immobilizing the device ofExample 1 while the trocar is withdrawn over both the device and theobturator. The obturator is then removed, leaving the implant behind ina well-controlled position. The edges of the incision are then securedwith a skin closure. The area is covered and kept dry for 2 to 3 days.

Example 3 Removal of the Device of Example 1

The device of Example 1 is removed as follows: The device is located byfingertip palpation of the upper arm area. The area at one end of theimplant is then anesthetized and an approximately 4 mm, perpendicularincision is made through the skin and any fibrous capsule tissuesurrounding the implant area. The end of the device opposite theincision is pushed so that the device end proximal to the incision isurged out of the incision. Any further fibrotic tissue is cut with ascalpel. Following removal, the procedure of Example 2 can be followedto insert a new device.

Example 4 Delivery Rate of the Device of Example 1

Glass test tubes were filled with 35 ml distilled water and then placedin a 37° C. water bath. A single device as described in Example 1 wasplaced in each test tube and the test tubes were changed periodically.The delivery rate profile from the system is shown in FIG. 9. The systemdoes not have any start-up time because the system exhibits a period ofinitial high release followed by a lower steady state release for aperiod of 200 days.

Example 5 Delivery Rate Profiles

Glass test tubes were filled with 35 ml distilled water which were thenplaced in a 37° C. water bath. After the test tubes had come up totemperature, a single device as described in Example 1, but withmembrane materials described below and containing 1% FD&C blue dye inwater as the drug formulation, was placed in each tube. Water from thetest tube permeated through the membrane causing the system to pumpformulation (blue dye) into the surrounding water in the test tube. Atregular intervals, systems were switched to fresh test tubes. The amountof dye released was determined by measuring the concentration of bluedye in each test tube using a spectrophotometer. The pumping rate wascalculated from the total dye released, the volume of water in the tube,the initial concentration of dye and the interval over which the systemwas in the test tube. Results for two different tests are shown in FIGS.10 and 11. FIG. 10 shows 3 different systems with different plugmaterials (Hytrel® 2, 3 and 12 month systems) and FIG. 11 shows 4systems with different plug materials. These materials are:

Membrane Material 1 month Pebax 25 (Polyamide) 2 month Pebax 22(Polyamide) 3 month Polyurethane (HP60D) 12 month  Pebax 24 (Polyamide)

The systems were capable of delivering for a period of from 2 to 12months, depending on the membrane used.

Example 6 Preparation of a Delivery Device with a Titanium Reservoir

A system containing leuprolide acetate for the treatment of prostatecancer was assembled from the following components:

Reservoir (Titanium, Ti6Al4V alloy) ( 4 mm outside diameter, 3 mm insidediameter)

Piston (C-Flex®)

Lubricant (silicone medical fluid)

Compressed osmotic engine (76.4 % NaCl, 15.5% sodium carboxymethylcellulose, 6% povidone, 0.5% Mg Stearate, 1.6% water)

PEG 400 (8 mg added to osmotic engine to fill air spaces)

Membrane plug (polyurethane polymer, injection molded to desired shape)

Back diffusion Regulating Outlet (polyethylene)

Drug formulation (0.150 g of 60% water and 40% leuprolide acetate)

Assembly

The piston and inner diameter of the reservoir were lightly lubricated.The piston was inserted ˜0.5 cm into the reservoir at the membrane end.PEG 400 was added into the reservoir. Two osmotic engine tablets (40 mgeach) were then inserted into the reservoir from the membrane end. Afterinsertion, the osmotic engine was flush with the end of the reservoir.The membrane plug was inserted by lining up the plug with the reservoirand pushing gently until the retaining features of the plug were fullyengaged in the reservoir. Formulation was loaded into a syringe whichwas then used to fill the reservoir from the outlet end by injectingformulation into the open tube until the formulation was ˜3 mm from theend. The filled reservoir was centrifuged (outlet end “up”) to removeany air bubbles that have been trapped in the formulation duringfilling. The outlet was screwed into the open end of the reservoir untilcompletely engaged. As the outlet was screwed in, excess formulationexited out of the orifice ensuring a uniform fill.

Example 7 Preparation of a Leuprolide Acetate Delivery Device with aTitanium Reservoir

A system containing leuprolide acetate for the treatment of prostatecancer was assembled from the following components:

Reservoir (Titanium Ti6Al4V alloy) (4 mm outside diameter, 3 mm insidediameter, 4.5 cm length)

Piston (C-Flex® TPE elastomer, available from Consolidated PolymerTechnologies, Inc.)

Lubricant (silicone medical fluid 360)

Compressed osmotic engine tablet (76.4% NaCl, 15.5% sodium carboxymethylcellulose, 6% povidone, 0.5% Mg Stearate, 1.5% water, 50 mg total)

PEG 400 (8 mg added to osmotic engine to fill air spaces)

Membrane plug (polyurethane polymer 20% water uptake, injection moldedto desired shape 3 mm diameter×4 mm length)

Back-diffusion Regulating Outlet (polyethylene, with 6 mil×5 cm channel)

Drug formulation (leuprolide acetate dissolved in DMSO to a measuredcontent of 65 mg leuprolide)

Assembly

Systems were assembled as in Example 6, using aseptic procedures toassemble γ-irradiated subassemblies and filled aseptically with sterilefiltered leuprolide DMSO formulation.

Release Rate

These systems delivered about 0.35 μL/day leuprolide formulationcontaining on average 150 μg leuprolide in the amount delivered per day.They provide delivery of leuprolide at this rate for at least one year.The systems achieved approximately 70% steady-state delivery by day 14.

Implantation and Removal

Systems will be implanted under local anesthetic and by means of anincision and trocar as in Example 2 to patient suffering from advancedprostatic cancer.

After one year, systems will be removed under local anesthetic asdescribed in Example 3. New systems may be inserted at that time.

Example 8 Treatment of Prostatic Cancer

Leuprolide acetate, an LHRH agonist, acts as a potent inhibitor ofgonadotropin secretion when given continuously and in therapeutic doses.Animal and human studies indicate that following an initial stimulation,chronic administration of leuprolide acetate results in suppression oftesticular steroidogenesis. This effect is reversible upondiscontinuation of drug therapy. Administration of leuprolide acetatehas resulted in inhibition of the growth of certain hormone-dependenttumors (prostatic tumors in Noble and Dunning male rats and DMBA-inducedmammary tumors in female rats) as well as atrophy of the reproductiveorgans. In humans, administration of leuprolide acetate results in aninitial increase in circulating levels of luteinizing hormone (LH) andfollicle stimulating hormone (FSH), leading to a transient increase inlevels of the gonadal steroids (testosterone and dihydrotestosterone inmales). However, continuous administration of leuprolide acetate resultsin decreased level of LH and FSH. In males, testosterone is reduced tocastrate levels. These decreases occur within two to six weeks afterinitiation of treatment, and castrate levels of testosterone inprostatic cancer patients have been demonstrated for multiyear periods.Leuprolide acetate is not active when given orally.

Systems will be prepared as in Example 7, then inserted as described.The continuous administration of leuprolide for one year using thesesystems will reduce testosterone to castrate levels.

The above description has been given for ease of understanding only. Nounnecessary limitations should be understood therefrom, as modificationswill be obvious to those skilled in the art.

1-50. (canceled)
 51. An implantable, fluid-imbibing device fordelivering an active agent to a fluid environment of use, said devicecomprising the following components: an impermeable reservoir comprisingan interior surface; a piston that divides the reservoir into awater-swellable agent chamber and an active agent chamber, wherein thewater-swellable agent chamber has an open end and the active agentformulation chamber has an open end; the active agent chamber comprisingan active agent formulation comprising the active agent; thewater-swellable agent chamber comprising a water-swellable agent; a backdiffusion regulating outlet received in the open end of the active agentformulation chamber of the reservoir for delivering fluid from theactive agent formulation chamber to the fluid environment, the reservoirinterior surface and back diffusion regulating outlet having surfaces ina mating relationship; and a water-swellable semipermeable plug receivedin sealing relationship with the interior surface of the open end of thewater-swellable agent chamber of the reservoir, wherein thesemipermeable plug imbibes between about 0.1% and about 200% by weightof water.
 52. The implantable, fluid-imbibing device of claim 51,wherein the semipermeable plug has an aspect ratio of between 1:10 and10:1 length to diameter.
 53. The implantable, fluid-imbibing device ofclaim 52, wherein the semipermeable plug has an aspect ratio of between7:10 and 2:1 length to diameter.
 54. The implantable, fluid-imbibingdevice of claim 52, wherein the semipermeable plug has an aspect ratioof about 1:2 length to diameter.
 55. The implantable, fluid-imbibingdevice of claim 51, wherein the reservoir interior surface and backdiffusion regulating outlet have surfaces in a mating relationship, ahelical flow path for the active agent formulation is formed between themating surfaces, a length of the helical flow path is sufficient toprevent back-diffusion of external fluid through the helical flow path,and the helical flow path has a length of about 2 to about 7 cm.
 56. Theimplantable, fluid-imbibing device of claim 51, wherein the reservoirinterior surface and back diffusion regulating outlet have surfaces in amating relationship, a helical flow path for the active agentformulation is formed between the mating surfaces, a length of thehelical flow path is sufficient to prevent back-diffusion of externalfluid through the helical flow path, and the helical flow path has adiameter of about 0.001 to about 0.020 inches.
 57. The implantable,fluid-imbibing device of claim 51, wherein the semipermeable plugcomprises a material selected from the group consisting of plasticizedcellulosic materials, polyurethanes, hydroxyethylmethacrylate,polyether-polyamide copolymers, and polyamides.
 58. The implantable,fluid-imbibing device of claim 51, wherein the water-swellable agentcomprises two tablets comprising sodium chloride.
 59. The implantable,fluid-imbibing device of claim 58, wherein the water-swellable agentchamber further comprises an additive to exclude air from spaces aroundthe water-swellable agent.
 60. The implantable, fluid-imbibing device ofclaim 59, wherein the additive is polyethylene glycol.
 61. Theimplantable, fluid-imbibing device of claim 51, wherein the reservoircomprises a material selected from the group consisting of anon-reactive polymer, a biocompatible metal, and a biocompatible metalalloy.
 62. The implantable, fluid-imbibing device of claim 61, whereinthe reservoir comprises a non-reactive polymer selected from the groupconsisting of acrylonitrile polymers and halogenated polymers.
 63. Theimplantable, fluid-imbibing device of claim 61, wherein the reservoircomprises a non-reactive polymer selected from the group consisting ofacrylonitrile-butadiene-styrene terpolymers; polytetrafluoroethylenes;polychlorotrifluoroethylenes; copolymer tetrafluoroethylenes;hexafluoropropylenes; polyimides; polysulfones; polycarbonates;polyethylenes; polypropylenes; polyvinylchloride-acrylic copolymers;polycarbonate-acrylonitrile-butadiene-styrenes; and polystyrenes. 64.The implantable, fluid-imbibing device of claim 61, wherein thereservoir comprises a biocompatible metal or a biocompatible metal alloyselected from the group consisting of stainless steel, titanium,platinum, tantalum, gold, stainless steel alloys, titanium alloys,platinum alloys, tantalum alloys, gold alloys, gold-plated ferrousalloys, platinum-plated ferrous alloys, cobalt-chromium alloys, andtitanium nitride coated stainless steel.
 65. The implantable,fluid-imbibing device of claim 64, wherein the reservoir comprisestitanium or a titanium alloy.
 66. The implantable, fluid-imbibing deviceof claim 65, wherein the reservoir comprises greater than 60% titaniumor a titanium alloy.
 67. The implantable, fluid-imbibing device of claim66, wherein the reservoir comprises greater than 85% titanium or atitanium alloy.
 68. The implantable, fluid-imbibing device of claim 51,wherein the piston comprises an elastomeric material.
 69. Theimplantable, fluid-imbibing device of claim 51, wherein the pistoncomprises a material selected from the group consisting ofpolypropylene, EPDM, silicone rubber, butyl rubber, plasticizedpolyvinylchloride, and polyurethanes.
 70. The implantable,fluid-imbibing device of claim 51, wherein the back diffusion regulatingoutlet is made of an insert, biocompatible material.
 71. Theimplantable, fluid-imbibing device of claim 70, wherein the inert,biocompatible material of the back diffusion regulating outlet comprisesa polymer.
 72. The implantable, fluid-imbibing device of claim 71,wherein the inert, biocompatible material of the back diffusionregulating outlet comprises a polymer selected from the group consistingof polyethylene, polypropylene, polycarbonate andpolymethylmethacrylate.
 73. The implantable, fluid-imbibing device ofclaim 70, wherein the inert, biocompatible material of the backdiffusion regulating outlet comprises a metal.
 74. The implantable,fluid-imbibing device of claim 51, wherein the active agent is selectedfrom the group consisting of a peptide and a protein.
 75. Theimplantable, fluid-imbibing device of claim 51, wherein one or morecomponent is sterilized.
 76. The implantable, fluid-imbibing device ofclaim 75, wherein the one or more component is sterilized using a methodselected from the group consisting of gamma radiation, steamsterilization, and sterile filtration.